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Prediction of response to treatment with phenelzine in neurotic patients
Prog.
Nmro-Psychopharmacot.
Pergamon
Press
Ltd,
Vol.4, pp.303-308. 1980. Printed in Great Britain.
PREDICTION
OF RESPONSE TO TREATMENT NEUROTIC PATIENTS
CHRISTOPHER Q. MO&JO& ROGER F. 12Department of Psychiatry, Department of Psychological 3 Institute of Psychiatry, (Final
WITH
PHwlsLzINB
IN
ELIZABEIH P. MARSHALL2 , IAIN C. CAMPBELL3 GARSIDE and MARTIN ROTH University of Cambridge Clinical School Medicine, University of Newcastle upon Tyne, England De Crespigny Park, London form,
April,
1980)
Abstract 1. 2.
3.
The records of patients completing a double blind trial of phenelzine and diazepam, and placebo and diazepam were examined to see if any pretreatment features were associated with response to phenelzine. There was no evidence of a difference in pattern of response between the two treatment groups. Initial biochemical values; acetylator status and premorbid personality features were not associated with improvement. Some anxious and phobic symptomatology was positively correlated with improvement. Depressive symptomatology was poorly negatively correlated with improvement. It was not possible in the present study to predict response to treatment from pretreatment variables. Introduction
The efficacy of the monoamine oxidase inhibitor phenelzine (Nardil) in the treatment of' neurotic illness has been the subject of controversy for several years and the results of controlled clinical trials have proved contradictory. Differing results in these trials cannot be explained by methodological variations alone though Tyrer (1976) has argued that the difference in outcome depends on the interaction between the dose and duration of treatment. Others have suggested that the different results may be caused by the presence of specific phenelsine responders, unfettered by diagnostic boundaries, who may have been over or under represented in the different trials. In support of this, Hamilton (1975) has shown that there are separate populations of phenelsine and imipramine responders in both endogenous and neurotic depressive diagnostic groups. Attempts have been made by a number of investigators to identify the characteristics which predict response to monoamine oxidase inhibitors. West and Dally (1959) and'sargant and Slater (1972) reported that responders were found in patients of good premorbid personality who typically tended to be overconscientious, sensitive, highly strung people with a lot of While similar energy and drive and who suffered from an atypical or hysterical depression. symptom profiles of atypical depression have been noted as predicting clinical response (Robinson et al, 1973; Ravaris et al, 1976; Tyrer, 1976), other groups have failed to find such a profile (Hutchinson and Smedberg, 1960; Kay et al, 1973; Raskin et al, 1974). Kay et al, (1973) also reported that a high N score on the Eysenck Personality Inventory predicted, a poor response to phenelsine. .: Bates and notable that Robinson et multicentre Robinson et significantly
Douglas (1961) suggested that outpatients fared better than inpatients and it the positive studies of Johnstone and Marsh (1973), Tyrer et al, (1973), al, (1973), Ravaris et al, (1976) dealt with outpatients while the negative trial of Raskin et al, (1974) and the MRC trial (1965) dealt with inpatients. al, (1974) found a differential response between the sexes with men respondidg better to treatment with phenelzine than women.
303
is
204
C. Q. Mountjoy
et al.
Johnstone and Marsh (1973) and Johnstone (1976) showed that fast acetylators failed to do significantly better than placebo treated patients while slow acetylators improved. Robinson et al, (1973), Ravaris et al, (1976) and Robinson et al, (1974) have reported that the degree of monoamine oxidase inhibition is of value in determining response to treatment. Both low levels of monoamine oxidase inhibition and the presence of fast acetylators have therefore been suggested as factors in the failure of some trials to show a therapeutic .response to phenelsine. The search for pretreatment biochemical measurements which predict response has proved unfruitful though Robinson et al, (1974) suggested that a high initial level of monoamine oxidase activity predicts a poor response to phenelzine treatment. In thfs paper, data from a controlled trial of phenelzine is used to try features which could predict a satisfactory response to phenelsine.
to identify
any
Method inpatients and A total of.117 patients of either sex, aged between 17 and 65 inclusive, outpatients, with a clinical diagnosis of neurotic depression (43), anxiety neurosis (44) or agoraphobia (30). entered the trial. Criteria for inclusion and exclusion have been described elsewhere (Mountjoy et al 1977). In summary patients with endogenous depression, schizophrenia, organic cerebral disease, alcoholism and obsessive compulsive neurosis were excluded as were patients who were unwilling to cooperate or who had failed to respond to adequate treatment with a monoamine oxidase inhibitor in the previous six months. After a period of seven days treatment with only diasepam 5 mg. thrice daily and nitrasepam as required at night, patients were randomly and blindly allocated within diagnostic groups to additional treatment with phenelzine or placebo. The dose of phenelzine was 45 mg. daily for two weeks, followed by 75 mg. daily for a further two weeks. Patients receiving placebo had the equivalent number of tablets. There was no statistically significant difference between randomly allocated treatment groups in respect of age, sex, social class, duration of treatment or the mean daily dose of diasepam. Clinical items of premorbid personality and symptomatology were rated routinely on a standard proforma on entry to the trial. In addition patients were scored on a diagnostic scale (Gurney et al, 1972) and on the Maudsley Personality Inventory (MPI). The rating scales used as measures of progress were: a four-point global rating scale, the Hamilton Anxiety Rating Scale (Hamilton, 1959), the Hamilton Depression Rating Scale (Hamilton, 1960), phobic scales for agoraphobia and social phobia (Gelder and Marks, 1966), using a five-point scale, the Wakefield, Modification of the Zung Self-Rating Scale (Snaith et al, 1971) and a Self-Rating Scale for anxiety (Lipsedge et al, 1971). All scales were administered before the start of the trial and repeated at weekly intervals, with the exception of the Hamilton scales which were repeated fortnightly. The statistical analyses in this report refer only to information available for the 83 patients, 38 phenelzine and 45 placebo treated, who completed four weeks treatment. The criterion for improvement is a principal component of improvement, derived from a factor analysis of the four week improvement scores of all the rating scales using in the trial. This component accountsfor 57% of the variance. The biochemical variables measured were, whole blood monoamine oxidase (MAO) measured by the method of Robinson et al, (1968) and modified by Marshall and Campbell (1977); whole blood 5hydroxytryptamine (5-HT), Yuwiler, et al (1970); uptake of 5-HT into blood platelets (Marshall et al, 1960; Campbell and Todrick, 1973), urinary 5 hydroxyindole-acetic acid (5HlAA) (Contractor, 1966) and urinary vanilymandelic acid @MA) (Pisano et al, 1962). Acetylator phenotype was determined by the method of Schroder (1972). Two samples of blood and urine were collected prior to treatment and it is the averaged pretreatment values which are used as the biochemical variables in this paper. Results A series of separate multiple regression analyses using symptoms, premorbid personality items and biochemical measurements as independent variables and the principal component of improvement as the dependent variable were performed on the phenelzine and placebo treated
Prediction
patients patterns difference biochemical
and on the of regression was found values.
combined group. coefficients in respect of
to
response
The results were by the method of premorbid personality,
Correlation coefficients between the premorbid and pretreatment biochemical tailed probability in patients who had statistically significant correlations premorbid personality variables. For negatively and fear of telephoning in 5% level of probability but at the 10% intolerance to noise, early wakening, of leaving the house and dizzy attacks negative correlation was found between significance. Depressive symptoms such persistence of depression and suicidal ly with improvement.
coefficients in phenelzine
between treated
phenelzine
305
tested for Rao (1952). clinical
in
clinical patients.
1 variables
and
principal
Correlation Coefficients Fear of telephoning in pub1 ic Situational phobias Dizzy attacks Fear of leaving the house Persistent fears Fear of public transport Early awakening Intolerance of noise Poor memory Episodic tension Depressed mood Persistent depression Reactivity of depression Suicidal tendencies
significant difference No significant pattern symptomatology or
principal component of improvement and the clinical, variables were calculated together with their two been treated with phenelzine. There are no found with the pretreatment biochemical values or clinical symptoms, episodic tension correlated public correlated positively with improvement at the level the additional features of persistent tension, situational phobias, fear of public transport, fear were also significantly directly correlated. A poor memory and outcome at the 10% level of as depressed mood, reactivity of depression, acts correlated negatively, weakly and non signficant-
Table Correlation improvement
to
component
of
Probability
0.005 0.052 0.063 0.064 0.065 0.074 0.099 0.099 0.51 0.03 0.808 0.604 0.407 0.436
0.459 0.32 0.318 0.31 0.32 0.296 0.27 0.27 -0.33 -0.37 -0.04 -0.086 -0.138 -0.13
Correlations between the principal component of improvement and the diagnostic scale score (Gurney et al, 1972) showed a significant positive correlation in the combined group. (r=0.3, p 0.006) and just failed to reach significance in phenelzine (r=0.31 p 0.057) and The N score of the Maudsley Personality placebo treated groups (r=0.29, p 0.052). The E score was significantly Inventory (MPI) did not correlate significantly with outcome. but not in the combined or phenelzine treated groups negatively correlated in the placebo, (r= -0.36 p 0.014; r= -0.197 p 0.075; r= -0.056 p 0.736 respectively). A one way analysis of covariance performed separately for no treatment effect in the fast acetylators and a significant not the second fortnight of treatment in the group of slow
fast
and slow improvement acetylators.
acetylators in the first
shows but
C. Q. Mountjoy
Fig.
1.
Clinical
Improvement
et al.
and Acetylator
Phenotype:
Two way-___ analysis_____-----_------of covariance. ----__
.................... r
Time (in Treatment
weeks): effect:
Acetylator
:
:
p<. 05
p-. 25
-
-
0
phenotype
effect:
Interaction effect: (between Treatment and AcetylaW Phenotype)
A two way signficantly was observed at a higher or phenotypes.
l
Phenelzlne
treated
slow fast slow fast
a
Phenelzlne
*
Placebo
treated treated
0
Placebo
treated
aCetylatOr:
acetylator: acetylator: acetylator.
analysis of covariance on this data (Fig. 1) indicates that phenelzine causes more improvement than placebo after two weeks, but no significant difference between the fast and slow acetylators. After a further two weeks of treatment dosage there was no significant difference in improvement between treatments
One way analyses of covariance calculated separately for inpatients and outpatients; males and females; and for those with more or less than 80% inhibition of monoamine oxidase showed no significant differences between treatment on the principal component of improvement. Discussion The results clearly show that biochemical measures including percentage inhibition of MAO and acetylator phenotype, did not predict response to phenelzine. The results concerning the acetylator phenotype are of particular interest for initially they appeared to confirm the results of Johnstone and Marsh (1973) and Johnstone (1976) yet there is clearly no evidence of an interaction effect due to phenotype in the two way analysis of covariance. Marshall (1976) has drawn attention to the lack of evidence that phenelzine is acetylated in man; such evidence as there is including our own (Marshall et al, 1978) is indirect. The failure to demonstrate monoamine oxidase inhibition
any difference is disappointing
in response between high and low levels as it seemed to promise a satisfactory
of way of
Prediction
monitoring methods
treatment. assessment
of
may be monoamine
The lack surprising
of as
of
between males such differences
The lack demonstrate "neuroticism" treatment
of
of
difference reports
significant significant or a "poor with phenelzine.
It
to
correlations correlations premorbid
that the oxidase and
response
to
difference activity.
307
phenelzine
in
females and were occasional.
this
finding
inpatients
is
and
with the N score of the MPI and with premorbid personality features personality" should not be regarded
due
to
the
outpatients
different
is
the
failure suggests as a bar
not
to that to
Although the correlations obtained were low, it is notable that the clinical symptoms significantly correlated with response to phenelzine are almost entirely those of anxiety and phobias and are similar to the features originally described by West and Dally (1959). This, together with the weak negative correlations with depressive symptomatology makes one consider the appropriateness of calling monoamine oxidase inhibitors anti-depressive drugs. Conclusion Our finding, appropriately treatment of
in common with many others, exhibited for the treatment depressive symptoms.
of
suggest phobic
that and
phenelzine anxiety
and symptoms
diazepam than
are for
more the
References BATES, T.J.N. and DOUGLAS, A.D. McL. (1961) A comparative trial of four mono-amine oxidase inhibitors on chronic depressives. .I. Ment. Sci. 107: 538-546. CAMPBELL, I.C. and TODRICK, A. (1973) On the pharmacology and biochemistry of the amineuptake mechanism in human blood platelets. Brit. J. Pharmacol. 49: 279-287. CONTRACTOR, S.F. (1966) A rapid quantitative method for the esxmation of 5-hydroxyindole-acetic acid in human urine. Biochem. Pharmacol. 15: 1701-170. GELDER, M.G. and MARKS, I.M. (1966) Severe agoraphobia: A controlled prospective trial of behaviour therapy. Brit. J. Psychiat. 112: 309-319. GURNEY, C., ROTH, M., GARSIDE, R.F., KEm7T.A. and SCHAPIRA, K. (1972) Studies in the classification of affecive disorders, the relationship between anxiety states and depressive illness. II. Brit. J. Psychiat. 121: 162-166. (1959) Assessment ofanxiety states by rating. Brit. J. Med. Psychol. HAMILTON, M. 32: 50-55. (1960) A rating scale for depression. J. Neurol. Neurosurg. Psychiat. -HAMILTON, M. 23: 56-62. In: Neuropsychopharmacology, -HAMILTON, M. (1975) Therapeutic effects of phenelzine. J.R. Boissier, H. Hippius and, P. Pichot (eds) pp. 782-787 Excerpta Medica International Congress Series 359. HUTCHINSON, J.T. and SMEDBERG, D. (1960) Phenelsine (Nardil) in the treatment of 704-710. endogenous depression. J. Ment. Sci. 106: JOHNSTONE, E.C. and MARSH, W. (1973) xetylator status and response to phenelzine in depressed patients. Lancet 1: 567-570. JOHNSTONE, E.C. (1976) Th; relationship between acetylator status and inhibition of monoamine oxidase excretion of free drug and antidepressant response in depressed patients on phenelzine. Psychopharmacologia (Berl) 46: 289-294. KAY, D.W.K., GARSIDE, R.F. and FAHY, T.J.71973) A double-blind trial of phenelzine and amitriptyline in depressed outpatients. A possible differential effect of the drugs on symptoms. Brit. J. Psychiat. 123: 63-67. LIPSEDGE, M.S., REES, W.L. andPIKE, D.J. (1971) A double-blind comparison of dothiepin Psychophatmacologia (Berl) and amitriptyline for the treatment of depression and anxiety. 19: 153-162. The effect of -MARSHALL, E.F., STIRLING, G.S., TAIT, A.C. and TODRICK, A. (1960). Brit. J. iproniazid and imipramine on the blood platelet 5-hyroxytryptamine level in man. Pharmacol.and Chemotherapy. 15: 35-41. (1976) Themyth ofphenelzine acetylation. Brit. Med. J. 817. MARSHALL, E.F. -ii:
C.
308
Q.
Mountjoy
et al.
MARSHALL, E.F. and CAMPBELL. I.C. (1977) A method for the determination of platelet and plasma monoamine oxidase in whole blood. Biochem. Pharmacol. 26: 353-354. MARSHALL, E.F., MOUNTJOY, C.Q., CAMPBELL, I.C., GARSIDE, R.F. YEITCH, 1-M. and ROTH, M. (1978) The influence of acetylator phenotype on the outcome of treatment with phenelzine in a clinical trial. Brit. J. Clin. Pharmacol. 6: 247-254. MOUNTJOY, C.Q., ROTH, M., GARSIDE, R.F. and LEITCH, I.M. (1977) A clinical trial of Brit. J. Psychiat. 131: 486-492. phenelzine in anxiety, depressive and phobic neuroses. MEDICAL RESEARCH COUNCIL REPORT (1965) Clinical trial of the treatment ofdepressive illness. Brit. Med. J. i: 881-886. PISANO, J.J., CROUT, J.R. and ABRAHAM, D. (1962) Determination of 3-methoxy285-291. 4-hydroxymandelic acid in urine. Clin. Chem. Acta. 7: RAO, C.R. (1952) Advanced statistical methods in bTometric research, pp. 112-115. John Wiley, New York. RASKIN, A., SCHULTERBRANDT, J.G., REATIG, N., CROOK, T.H. and ODLE, D. (1974) Depressior Arch. Gen. Psychiat. subtypes and response to phenelzine, diazepam and a placebo. -30: 66-75. RAVARIS, C.L., NIES, A., ROBINSON, D.S., IVES, J.O., LAMBORN, K.R. and KORSON, L. (1976) A multiple-dose, controlled study of phenelzine in depression anxiety states. Arch. Gen. Psychiat. 33: 347-350. ROBINSON,O.S., LOVENBERG, W., KEISER, H. and SJOERDSMA, A. (1968) Effects of drugs on human blood platelets and plasma amine oxidase activity in vitro and in viva. Biochem. Pharmacol. 17: 109-119. ROBINSON, ES., NIES, A., RAVARIS, C.L. and LAMBOURN, K.R. (1973) The monoamine oxidase inhibitor, phenelzine, in the treatment of depressive-anxiety states. Arch. Gen. Psychiat. 29: 407-413. ROBINSON, D.S., NIES, A., RAVARIS, C.L., IVES, J.O. and LAMBOURN, K.R. (1974) Treatment to MAO inhibitors: Relation to depressive typology and blood platelets MAO inhibitors. pp. 259-267 In: Classification and Prediction of Outcome of Depression. Symposia Medica Hoechst 8. F. K. Schattauer Verlag, Stuttgart. SARGANT, W. and SLATER, E. (1972) An introduction to physical methods of treatment in psychiatry. pp.45. 5th ed. Churchill Livingstone, Edinburgh and London. SCHRODER, M. (1972) Simplified method of determining acetylator phenotype. Brit. Med. J. iii: 506-507. SNmH, R.P., AHMED, S.N., MEHTA, S. and HAMILTON, M. (1971) Assessment of the severity of primary depressive illness: Wakefield self-assessment depression inventory. Psychological Med. 1: 143-149. TYRER, P., CANDY, 5. and KELLY, D. (1973) Phenelzine in phobic anxiety: a controlled trial. Psychological Med. 3: 120-124. TYRER, P. (1976) Towards rational therapy with monoamine oxidase inhibitors. Brit. J. Psychiat. 128: 354-360. WEST, E.Dxnd DALLY, P.J. (1959) Effects of iproniazid in depressive syndromes. Brit. i: Med. J. 1491-1494. YUWILER, A., PLOTKINS, S., GELLER, E. and RITVO, E.R. (1970) A rapid accurate procedure for the determination of serotonin in whole human blood. Biochem. Med. -3: 426-431.
Inquiries
and
reprint
Dr. C. Q. Mountjoy Department of Psychiatry, Level 4, Addenbrooke's Hills Road, Cambridge
requests
should
University of Hospital CB2 2QQ, England
be
addressed
Cambridge
to:
Clinical
School
Nmro-Psychopharmacot.
Pergamon
Press
Ltd,
Vol.4, pp.303-308. 1980. Printed in Great Britain.
PREDICTION
OF RESPONSE TO TREATMENT NEUROTIC PATIENTS
CHRISTOPHER Q. MO&JO& ROGER F. 12Department of Psychiatry, Department of Psychological 3 Institute of Psychiatry, (Final
WITH
PHwlsLzINB
IN
ELIZABEIH P. MARSHALL2 , IAIN C. CAMPBELL3 GARSIDE and MARTIN ROTH University of Cambridge Clinical School Medicine, University of Newcastle upon Tyne, England De Crespigny Park, London form,
April,
1980)
Abstract 1. 2.
3.
The records of patients completing a double blind trial of phenelzine and diazepam, and placebo and diazepam were examined to see if any pretreatment features were associated with response to phenelzine. There was no evidence of a difference in pattern of response between the two treatment groups. Initial biochemical values; acetylator status and premorbid personality features were not associated with improvement. Some anxious and phobic symptomatology was positively correlated with improvement. Depressive symptomatology was poorly negatively correlated with improvement. It was not possible in the present study to predict response to treatment from pretreatment variables. Introduction
The efficacy of the monoamine oxidase inhibitor phenelzine (Nardil) in the treatment of' neurotic illness has been the subject of controversy for several years and the results of controlled clinical trials have proved contradictory. Differing results in these trials cannot be explained by methodological variations alone though Tyrer (1976) has argued that the difference in outcome depends on the interaction between the dose and duration of treatment. Others have suggested that the different results may be caused by the presence of specific phenelsine responders, unfettered by diagnostic boundaries, who may have been over or under represented in the different trials. In support of this, Hamilton (1975) has shown that there are separate populations of phenelsine and imipramine responders in both endogenous and neurotic depressive diagnostic groups. Attempts have been made by a number of investigators to identify the characteristics which predict response to monoamine oxidase inhibitors. West and Dally (1959) and'sargant and Slater (1972) reported that responders were found in patients of good premorbid personality who typically tended to be overconscientious, sensitive, highly strung people with a lot of While similar energy and drive and who suffered from an atypical or hysterical depression. symptom profiles of atypical depression have been noted as predicting clinical response (Robinson et al, 1973; Ravaris et al, 1976; Tyrer, 1976), other groups have failed to find such a profile (Hutchinson and Smedberg, 1960; Kay et al, 1973; Raskin et al, 1974). Kay et al, (1973) also reported that a high N score on the Eysenck Personality Inventory predicted, a poor response to phenelsine. .: Bates and notable that Robinson et multicentre Robinson et significantly
Douglas (1961) suggested that outpatients fared better than inpatients and it the positive studies of Johnstone and Marsh (1973), Tyrer et al, (1973), al, (1973), Ravaris et al, (1976) dealt with outpatients while the negative trial of Raskin et al, (1974) and the MRC trial (1965) dealt with inpatients. al, (1974) found a differential response between the sexes with men respondidg better to treatment with phenelzine than women.
303
is
204
C. Q. Mountjoy
et al.
Johnstone and Marsh (1973) and Johnstone (1976) showed that fast acetylators failed to do significantly better than placebo treated patients while slow acetylators improved. Robinson et al, (1973), Ravaris et al, (1976) and Robinson et al, (1974) have reported that the degree of monoamine oxidase inhibition is of value in determining response to treatment. Both low levels of monoamine oxidase inhibition and the presence of fast acetylators have therefore been suggested as factors in the failure of some trials to show a therapeutic .response to phenelsine. The search for pretreatment biochemical measurements which predict response has proved unfruitful though Robinson et al, (1974) suggested that a high initial level of monoamine oxidase activity predicts a poor response to phenelzine treatment. In thfs paper, data from a controlled trial of phenelzine is used to try features which could predict a satisfactory response to phenelsine.
to identify
any
Method inpatients and A total of.117 patients of either sex, aged between 17 and 65 inclusive, outpatients, with a clinical diagnosis of neurotic depression (43), anxiety neurosis (44) or agoraphobia (30). entered the trial. Criteria for inclusion and exclusion have been described elsewhere (Mountjoy et al 1977). In summary patients with endogenous depression, schizophrenia, organic cerebral disease, alcoholism and obsessive compulsive neurosis were excluded as were patients who were unwilling to cooperate or who had failed to respond to adequate treatment with a monoamine oxidase inhibitor in the previous six months. After a period of seven days treatment with only diasepam 5 mg. thrice daily and nitrasepam as required at night, patients were randomly and blindly allocated within diagnostic groups to additional treatment with phenelzine or placebo. The dose of phenelzine was 45 mg. daily for two weeks, followed by 75 mg. daily for a further two weeks. Patients receiving placebo had the equivalent number of tablets. There was no statistically significant difference between randomly allocated treatment groups in respect of age, sex, social class, duration of treatment or the mean daily dose of diasepam. Clinical items of premorbid personality and symptomatology were rated routinely on a standard proforma on entry to the trial. In addition patients were scored on a diagnostic scale (Gurney et al, 1972) and on the Maudsley Personality Inventory (MPI). The rating scales used as measures of progress were: a four-point global rating scale, the Hamilton Anxiety Rating Scale (Hamilton, 1959), the Hamilton Depression Rating Scale (Hamilton, 1960), phobic scales for agoraphobia and social phobia (Gelder and Marks, 1966), using a five-point scale, the Wakefield, Modification of the Zung Self-Rating Scale (Snaith et al, 1971) and a Self-Rating Scale for anxiety (Lipsedge et al, 1971). All scales were administered before the start of the trial and repeated at weekly intervals, with the exception of the Hamilton scales which were repeated fortnightly. The statistical analyses in this report refer only to information available for the 83 patients, 38 phenelzine and 45 placebo treated, who completed four weeks treatment. The criterion for improvement is a principal component of improvement, derived from a factor analysis of the four week improvement scores of all the rating scales using in the trial. This component accountsfor 57% of the variance. The biochemical variables measured were, whole blood monoamine oxidase (MAO) measured by the method of Robinson et al, (1968) and modified by Marshall and Campbell (1977); whole blood 5hydroxytryptamine (5-HT), Yuwiler, et al (1970); uptake of 5-HT into blood platelets (Marshall et al, 1960; Campbell and Todrick, 1973), urinary 5 hydroxyindole-acetic acid (5HlAA) (Contractor, 1966) and urinary vanilymandelic acid @MA) (Pisano et al, 1962). Acetylator phenotype was determined by the method of Schroder (1972). Two samples of blood and urine were collected prior to treatment and it is the averaged pretreatment values which are used as the biochemical variables in this paper. Results A series of separate multiple regression analyses using symptoms, premorbid personality items and biochemical measurements as independent variables and the principal component of improvement as the dependent variable were performed on the phenelzine and placebo treated
Prediction
patients patterns difference biochemical
and on the of regression was found values.
combined group. coefficients in respect of
to
response
The results were by the method of premorbid personality,
Correlation coefficients between the premorbid and pretreatment biochemical tailed probability in patients who had statistically significant correlations premorbid personality variables. For negatively and fear of telephoning in 5% level of probability but at the 10% intolerance to noise, early wakening, of leaving the house and dizzy attacks negative correlation was found between significance. Depressive symptoms such persistence of depression and suicidal ly with improvement.
coefficients in phenelzine
between treated
phenelzine
305
tested for Rao (1952). clinical
in
clinical patients.
1 variables
and
principal
Correlation Coefficients Fear of telephoning in pub1 ic Situational phobias Dizzy attacks Fear of leaving the house Persistent fears Fear of public transport Early awakening Intolerance of noise Poor memory Episodic tension Depressed mood Persistent depression Reactivity of depression Suicidal tendencies
significant difference No significant pattern symptomatology or
principal component of improvement and the clinical, variables were calculated together with their two been treated with phenelzine. There are no found with the pretreatment biochemical values or clinical symptoms, episodic tension correlated public correlated positively with improvement at the level the additional features of persistent tension, situational phobias, fear of public transport, fear were also significantly directly correlated. A poor memory and outcome at the 10% level of as depressed mood, reactivity of depression, acts correlated negatively, weakly and non signficant-
Table Correlation improvement
to
component
of
Probability
0.005 0.052 0.063 0.064 0.065 0.074 0.099 0.099 0.51 0.03 0.808 0.604 0.407 0.436
0.459 0.32 0.318 0.31 0.32 0.296 0.27 0.27 -0.33 -0.37 -0.04 -0.086 -0.138 -0.13
Correlations between the principal component of improvement and the diagnostic scale score (Gurney et al, 1972) showed a significant positive correlation in the combined group. (r=0.3, p 0.006) and just failed to reach significance in phenelzine (r=0.31 p 0.057) and The N score of the Maudsley Personality placebo treated groups (r=0.29, p 0.052). The E score was significantly Inventory (MPI) did not correlate significantly with outcome. but not in the combined or phenelzine treated groups negatively correlated in the placebo, (r= -0.36 p 0.014; r= -0.197 p 0.075; r= -0.056 p 0.736 respectively). A one way analysis of covariance performed separately for no treatment effect in the fast acetylators and a significant not the second fortnight of treatment in the group of slow
fast
and slow improvement acetylators.
acetylators in the first
shows but
C. Q. Mountjoy
Fig.
1.
Clinical
Improvement
et al.
and Acetylator
Phenotype:
Two way-___ analysis_____-----_------of covariance. ----__
.................... r
Time (in Treatment
weeks): effect:
Acetylator
:
:
p<. 05
p-. 25
-
-
0
phenotype
effect:
Interaction effect: (between Treatment and AcetylaW Phenotype)
A two way signficantly was observed at a higher or phenotypes.
l
Phenelzlne
treated
slow fast slow fast
a
Phenelzlne
*
Placebo
treated treated
0
Placebo
treated
aCetylatOr:
acetylator: acetylator: acetylator.
analysis of covariance on this data (Fig. 1) indicates that phenelzine causes more improvement than placebo after two weeks, but no significant difference between the fast and slow acetylators. After a further two weeks of treatment dosage there was no significant difference in improvement between treatments
One way analyses of covariance calculated separately for inpatients and outpatients; males and females; and for those with more or less than 80% inhibition of monoamine oxidase showed no significant differences between treatment on the principal component of improvement. Discussion The results clearly show that biochemical measures including percentage inhibition of MAO and acetylator phenotype, did not predict response to phenelzine. The results concerning the acetylator phenotype are of particular interest for initially they appeared to confirm the results of Johnstone and Marsh (1973) and Johnstone (1976) yet there is clearly no evidence of an interaction effect due to phenotype in the two way analysis of covariance. Marshall (1976) has drawn attention to the lack of evidence that phenelzine is acetylated in man; such evidence as there is including our own (Marshall et al, 1978) is indirect. The failure to demonstrate monoamine oxidase inhibition
any difference is disappointing
in response between high and low levels as it seemed to promise a satisfactory
of way of
Prediction
monitoring methods
treatment. assessment
of
may be monoamine
The lack surprising
of as
of
between males such differences
The lack demonstrate "neuroticism" treatment
of
of
difference reports
significant significant or a "poor with phenelzine.
It
to
correlations correlations premorbid
that the oxidase and
response
to
difference activity.
307
phenelzine
in
females and were occasional.
this
finding
inpatients
is
and
with the N score of the MPI and with premorbid personality features personality" should not be regarded
due
to
the
outpatients
different
is
the
failure suggests as a bar
not
to that to
Although the correlations obtained were low, it is notable that the clinical symptoms significantly correlated with response to phenelzine are almost entirely those of anxiety and phobias and are similar to the features originally described by West and Dally (1959). This, together with the weak negative correlations with depressive symptomatology makes one consider the appropriateness of calling monoamine oxidase inhibitors anti-depressive drugs. Conclusion Our finding, appropriately treatment of
in common with many others, exhibited for the treatment depressive symptoms.
of
suggest phobic
that and
phenelzine anxiety
and symptoms
diazepam than
are for
more the
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